This application is a continuation-in-part of patent application Ser. No. 08/788,822, filed Jan. 23, 1997, which application is a continuation-in-part of provisional patent application No. 60/010,510, filed on Jan. 24, 1996. This application also claims priority to U.S. patent application Ser. No. 08/305,871, filed Sep. 14, 1994, now U.S. Pat. No. 5,736,142, issued Apr. 7, 1998, which is a continuation-in-part of application U.S. Ser. No. 08/121,101 filed Sep. 14, 1993, now abandoned, all of which are incorporated herein by reference.
The present invention relates to compositions and methods for preventing, treating or diagnosing a number of pathological states such as autoimmune diseases, viral diseases and cancers. In particular, it provides novel peptides capable of binding selected major histocompatibility complex (MHC) molecules and either inducing or inhibiting an immune response.
MHC molecules are classified as either Class I or Class II molecules. Class II MHC molecules are expressed by specialized antigen presenting cells (APC) such as macrophages, dendritic cells, or B cells. The Class II MHC molecules usually associate with peptide fragments derived from processing of protein antigens which enter the endocytic pathway from the APC exterior. The MHC-peptide complexes are subsequently presented for scrutiny to CD4+ T helper cells which are then activated, proliferate and amplify the immune response to the particular immunogenic peptide that is displayed. Activation of T cells requires engagement of the T Cell Receptor (TCR) by its ligand, a bi-molecular complex of an MHC molecule and a peptide antigen (Shimonkevitz, et al., J. Immunol. 133, 2067–2074 (1984); Babbitt, et al., Nature 317, 359–361 (1985); Buus, et al., Cell 47, 1071–1077 (1986); Townsend, A., and Bodmer, H., Annu. Rev. Immunol. 7, 601–624.
Inappropriate activation of T cells is a component of a number of immunopathologies, such as autoimmunity, allograft rejection and allergic responses. Exemplary autoimmune diseases include rheumatoid arthritis, multiple sclerosis, and myasthenia gravis. Allergic responses involving T cell activation include allergies to various pollens, dust mites and the like. In addition, foreign infectious diseases may cause immunopathology (e.g., lyme disease, hepatitis, LCMV, post-streptococcal endocarditis, or glomerulonephritis). Food hypersensitivities, such as celiac disease and Crohn's disease, as well as other allergic diseases, have been associated with particular MHC alleles or suspected of having an autoimmune component.
The most commonly used approach to treating these conditions is to suppress the immune system, typically by using immunosuppressive drugs. Another approach has been proposed for cases in which the MHC allele associated with the condition is known, involving selective blockade of a given MHC allele. However, where a number of MHC restrictions are involved, approaches other than selective blockade must be found.
Immunochemical studies of the requirements for peptide binding to class II molecules have been carried out. The binding motifs of several murine and human class II MHC alleles have been defined, and motif analysis by sequencing of naturally processed peptides has also recently been described for various class II types (Rudensky et al., Nature 353, 622–627 (1991); Chicz et al., Nature 358, 764–768 (1992); Hunt et al., Science 256, 1817–1820 (1992); Rudensky et al., Nature 359, 429–431 (1992)).
In the case of DR molecules in particular, it has been shown (Brown et al., Nature 364, 33–39 (1993)) that a large hydrophobic anchor engaging a corresponding hydrophobic pocket of the MHC binding groove is the most crucial determinant of peptide-DR interactions. Several other anchors play definite, albeit less prominent roles and help determine allelic specificity. Recently it has also been emphasized that the peptide backbone of the C-terminal half of the peptide molecule is engaged in direct hydrogen bonding with the walls of the MHC binding groove (Krieger et al., J. Immunol. 146, 2331–2340 (1991)); O'Sullivan et al., J. Immunol. 146, 1240–1246 (1991); and O'Sullivan et al., J. Immunol. 147, 2663–2669 (1991).
Although allele-specific polymorphic residues that line the peptide binding pockets of MHC alleles tend to endow each allele with the capacity to bind a unique set of peptides, there are many instances in which a given peptide has been shown to bind to more than one MHC specificity. This has been best documented in the case of the human DR isotype, in which it has been noted that several DR alleles appear to recognize similar motifs, and independently, several investigators reported degenerate binding and/or recognition of certain epitopes in the context of multiple DR types, leading to the concept that certain peptides might represent “universal” epitopes (Busch et al., Int. Immunol. 2, 443–451 (1990); Panina-Bordignon et al., Eur. J. Immunol. 19, 2237–2242 (1989); Sinigaglia et al., Nature 336, 778–780 (1988); O'Sullivan et al., J. Immunol. 147, 2663–2669 (1991) Roache et al., J. Immunol. 144, 1849–1856 (1991); Hill et al., J. Immunol. 147, 189–197 (1991)). However, although the previously reported epitopes do have the capacity to bind to several DR alleles, they are by no means universal.
Accordingly, the present invention provides DR binding peptides, called “pan DR binding peptides” that are recognized by a broad pattern of DR alleles. According to the present invention such Pan DR binding peptides may be used as potent immunogens for class II restricted T cells, and as a; useful human peptide-based immunosuppressant, vaccine or therapeutic agent.